

Item type: | Article | ||||
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Journal or Publication Title: | Cancer Research | ||||
Publisher: | AMER ASSOC CANCER RESEARCH | ||||
Place of Publication: | PHILADELPHIA | ||||
Volume: | 79 | ||||
Number of Issue or Book Chapter: | 6 | ||||
Page Range: | pp. 1239-1251 | ||||
Date: | 2019 | ||||
Institutions: | Biology, Preclinical Medicine > Institut für Biophysik und physikalische Biochemie Biology, Preclinical Medicine > Institut für Biophysik und physikalische Biochemie > Alumni or Retired > Prof. Dr. Eggehard Holler | ||||
Identification Number: |
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Keywords: | CELL MIGRATION; IN-VITRO; EXPRESSION; BRAIN; LAMININ-8; TARGET; HETEROGENEITY; EFFICACY; INVASION; PATHWAYS; | ||||
Dewey Decimal Classification: | 500 Science > 570 Life sciences | ||||
Status: | Published | ||||
Refereed: | Yes, this version has been refereed | ||||
Created at the University of Regensburg: | Yes | ||||
Item ID: | 48874 |
Abstract
There is an unmet need for the treatment of glioblastoma multiforme (GBM). The extracellular matrix, including laminins, in the tumor microenvironment is important for tumor invasion and progression. In a panel of 226 patient brain glioma samples, we found a clinical correlation between the expression of tumor vascular laminin-411 (alpha 4 beta 1 gamma 1) with higher tumor grade and with ...

Abstract
There is an unmet need for the treatment of glioblastoma multiforme (GBM). The extracellular matrix, including laminins, in the tumor microenvironment is important for tumor invasion and progression. In a panel of 226 patient brain glioma samples, we found a clinical correlation between the expression of tumor vascular laminin-411 (alpha 4 beta 1 gamma 1) with higher tumor grade and with expression of cancer stem cell (CSC) markers, including Notch pathway members, CD133, Nestin, and c-Myc. Laminin-411 overexpression also correlated with higher recurrence rate and shorter survival of GBM patients. We also showed that depletion of laminin-411 alpha 4 and beta 1 chains with CRISPR/Cas9 in human GBM cells led to reduced growth of resultant intracranial tumors in mice and significantly increased survival of host animals compared with mice with untreated cells. Inhibition of laminin-411 sup-pressed Notch pathway in normal and malignant human-brain cell types. A nanobioconjugate potentially suitable for clinical use and capable of crossing blood-brain barrier was designed to block laminin-411 expression. Nanobioconjugate treatment of mice carrying intracranial GBMsignificantly increased animal survival and inhibited multiple CSC markers, including the Notch axis. This study describes an efficient strategy for GBMtreatment via targeting a critical component of the tumor microenvironment largely independent of heterogeneous genetic mutations in glioblastoma. Significance: Laminin-411 expression in the glioma microenvironment correlates with Notch and other cancer stem cell markers and can be targeted by a novel, clinically translatable nanobioconjugate to inhibit glioma growth.
Metadata last modified: 03 Sep 2021 10:03